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Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: a Workshop Report

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Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: a Workshop Report Hindawi Canadian Respiratory Journal Volume 2020, Article ID 5852827, 16 pages https://doi.org/10.1155/2020/5852827 Review Article Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: A Workshop Report Silvija-PeraJerkic ,1 FolkeBrinkmann,2 AlistairCalder,3 AliciaCasey ,4 MeganDishop,5 Matthias Griese,6 Geoffrey Kurland,7 Mandy Niemitz,8 Sylvia Nyilas,9 Dirk Schramm,10 Ralf Schubert,1 Michael Tamm,11 Stefan Zielen ,1 and Martin Rosewich1 1Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, Goethe-University, Frankfurt/Main, Germany 2Department of Paediatric Pneumology, Children’s Hospital, Ruhr University of Bochum, Bochum, Germany 3Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK 4Boston Children’s Hospital, Harvard Medical School, Boston, USA 5Division of Pathology and Laboratory Medicine, Phoenix Children’s Hospital, Phoenix, USA 6Department of Pediatric Pneumology, Dr. von Hauner Children’s Hospital, LMU Munich, German Center for Lung Research (DZL), Munich, Germany 7Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, USA 8University of Ulm Medical Centre, Clinic for Child and Adolescent Psychiatry/Psychotherapy, Ulm, Germany 9Division of Respiratory Medicine, Department of Pediatrics, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland 10Department of General Pediatrics, University Children’s Hospital, Du¨sseldorf, Germany 11Department of Pulmonary Medicine, University Hospital Basel, Basel, Switzerland Correspondence should be addressed to Silvija-Pera Jerkic; [email protected] Received 27 August 2019; Revised 29 November 2019; Accepted 27 December 2019; Published 31 January 2020 Academic Editor: Motoshi Takao Copyright © 2020 Silvija-Pera Jerkic et al. ,is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Bronchiolitis obliterans (BO) is a rare, chronic form of obstructive lung disease, often initiated with injury of the bronchiolar epithelium followed by an inflammatory response and progressive fibrosis of small airways resulting in nonuniform luminal obliteration or narrowing. ,e term BO comprises a group of diseases with different underlying etiologies, courses, and characteristics. Among the better recognized inciting stimuli leading to BO are airway pathogens such as adenovirus and mycoplasma, which, in a small percentage of infected children, will result in progressive fixed airflow obstruction, an entity referred to as postinfectious bronchiolitis obliterans (PIBO). ,e present knowledge on BO in general is reasonably well de- veloped, in part because of the relatively high incidence in patients who have undergone lung transplantation or bone marrow transplant recipients who have had graft-versus-host disease in the posttransplant period. ,e cellular and molecular pathways involved in PIBO, while assumed to be similar, have not been adequately elucidated. Since 2016, an international consortium of experts with an interest in PIBO assembles on a regular basis in Geisenheim, Germany, to discuss key areas in PIBO which include diagnostic workup, treatment strategies, and research fields. 1. Introduction Lange described two cases of unknown origin [1]. Most early descriptions of BO were confined to case reports with Bronchiolitis obliterans (BO) is a rare, chronic form of autopsy findings; it was not until open lung biopsy became obstructive lung disease. ,e first report of BO in 1901 by a more common procedure possible to describe earlier 2 Canadian Respiratory Journal pathologic findings that suggested the cellular mecha- 3. Epidemiology nisms that ultimately led to BO. A review of the subject of BO in children summarized available studies suggesting PIBO is a rare disease but as there is no systematic case that BO begins with an injury of the bronchiolar epi- registration and as there are no national or international thelium followed by an inflammatory reaction which databases on PIBO, its incidence is unpredictable. ,e ep- progresses towards airway fibrosis and potential luminal idemiology is further hampered by a variable nomenclature. obliteration [2]. ,erefore, the frequency is largely unknown and possibly ,e term “bronchiolitis obliterans” likely describes a more frequent than expected, as many milder cases might common pathologic alteration of small airways following a remain undiagnosed. It is well known that PIBO is more variety of inciting diseases with different aetiologies and frequent among certain populations such as Argentinians, characteristics. ,e initial insult, the localized inflammatory Native Americans, and native Koreans [3–5] pointing to- response, and preexisting factors including nutritional status wards genetic factors playing a pivotal role in the initiation and genetic variants are felt to influence the process which or perpetuation of the process. finally leads to the observed pathology in small airways. BO following human stem cell transplantation (HSCT), HSCT- 4. Etiology BOS, complicated by graft-versus-host disease (GVHD) and BO following lung transplantation (LT), LT-BOS, have both BO is thought to be caused by an initial insult to the lower been extensively studied and are relatively well understood. airways [6]. However, there are three separate clinical en- Postinfectious BO (PIBO) in part because of its sporadic tities of BO. ,e severe injury to the lower respiratory tract appearance and low incidence has been much more difficult can be caused by either a pathogen such as adenovirus, to study. While there are study-based protocols for the influenza, measles, respiratory syncytial virus, and myco- evaluation and potential treatment of HSCT/GVHD and LT- plasma pneumonia (PIBO) or lung, heart (LT-BO), or bone related BO, the diagnosis and management of PIBO are not marrow transplantation (HSCT-BO) [3, 7]. In addition, as clear. A better understanding of the molecular and cellular some cases of BO were triggered by toxic gases [8], chronic mechanisms involved in the development of PIBO is needed aspiration [9], connective tissue diseases [10], and certain if more directed prevention and treatment strategies are to drugs [11]. ,e repair process of restoring the epithelium be uncovered. and microvasculature to its previous state is severely altered. Since 2016, an international consortium of experts ,is failure of resolution of the initial and ongoing consisting of pediatric pulmonologists, radiologists, pa- inflammation might be an important part of the disease thologists, physical therapists, psychologists, basic scien- process in PIBO. ,e influx of immune and inflammatory tists, and statisticians has gathered regularly for a cells and the proliferation of granulation tissue in the airways workshop on PIBO in Geisenheim, Germany. ,e work- lead to bronchial obstruction and to epithelial changes such shop has been complemented by affected families and as atrophy or hyperplasia [12]. representatives of the Foundation “Stiftung Starke Lunge” ,e etiology is used for clinical classification and is (http://www.starkelunge.de). ,e purpose of the work- important to guide the investigator to the diagnosis when shop has been to bring together international clinicians tachypnoea, wheezing, and hypoxaemia persist for at least 2 and researchers and to exchange and discuss new findings months after a causative event. Accordingly, most of the BO and current research data in the field of PIBO. ,e cases can be classified into postinfectious and posttransplant multidisciplinary workshop presentations have included BO [2]. definitions, epidemiology, etiology, and clinical courses of PIBO. ,e focus of the attendees has been set on specific 5. Clinical Course key areas which included diagnostic workup, treatment strategies, and research fields. In conclusion, future per- ,e diagnosis of PIBO is usually late as the initial presen- spectives and joint research goals were being discussed tation shows a large overlap with much more frequent and distributed. airway diseases, and many causative agents have been de- ,e following article serves as the first official workshop scribed. By the time of diagnosis, the airway disease is summary of an international consortium of experts in frequently advanced and irreversible fibrotic changes and PIBO. airway obliteration have been established making the treatment difficult and often unsuccessful. As disease pro- gression or disease stages are not defined yet, the recom- 2. Definition mendation of an appropriate treatment is further hindered by changes of inflammatory patterns over time. In the past, there have been several attempts to classify While the clinical course of BOS after HSCT has been the condition PIBO. However, none of the present def- described in the literature [13, 14], there are no existing initions are widely accepted. PIBO is a process charac- reviews summarizing the clinical course of PIBO. ,e terised by persistent airway obstruction with functional prognosis of PIBO seems to have a better outcome than and radiological evidence of small airway involvement HSCT-BOS and LT-BOS, respectively. However, the course that is in general unresponsive to bronchodilator varies in each case and therefore cannot be predicted. treatment. Empirical data reveals three different
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